EA004179B1 - Method of treating neoplastic disease for administration of phenylacetylglutamine, phenylacetylisoglutamine, and/or phenylacetate - Google Patents

Abstract

1. A pharmaceutical composition, comprising in aqueous solution (a) a compound of Formula I: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl(C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II: wherein X is a halogen, lower alkyl (C1-6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-12), or hydroxy and n is 0, 1, 2, 3, or 4; and b) a compound of formula III: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl (C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II; and wherein the compound of Formula I is present in a 4:1 ratio by weight to the compound of formula III and the combined concentration of the compound of Formula I and the compound of Formula III is from 200 mg/mL to 350 mg/ml. 2. The pharmaceutical composition of claim 1, wherein in the compound of Formula I, M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH; and wherein in the compound of Formula III, M is hydrogen or sodium; n is 0; R is selected from the group consisting of H and C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH. 3. The pharmaceutical composition of claim 1, wherein the compound of Formula I is phenylacetylglutamine or pharmaceutically acceptable salts thereof, and the compound of Formula III is phenylacetylisoglutamine or pharmaceutically acceptable salts thereof. 4. The pharmaceutical composition of claim 4, wherein the combined concentration is about 300 mg/mL. 5. A method of treating neoplastic disease, comprising: a) administering to a patient a pharmaceutical composition comprising: i) a compound of Formula IV: wherein n is 0-5; M is hydrogen, a salt forming cation, alkyl (C1-6), cycloalkyl, or aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II: wherein X is a halogen, lower alkyl (C1-6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-12), substituted aryl or hydroxy and n is 0, 1, 2, 3, or 4; and ii) a compound of Formula I: wherein n is 0-5; M is hydrogen, a salt forming cation, alkyl (C1-6), cycloalkyl, or aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II; wherein the compound of Formula IV and the compound of Formula I are present in a 4:1 ratio by weight; and iii) water sufficient to form an aqueous solution of the compound of Formula IV and the compound of Formula I wherein the combined concentration of the compound of Formula IV and the compound of formula I is from 70 mg/mL to 150 mg/mL, b) administering a composition at an infusion rate from 100 mL/hr to 400 mL/hr, wherein the composition is administered at a rate sufficient to reach a dosage level of from 0.1 g/kg/day to 2.6 g/kg/day, preferably from 0.2 g/kg/day to 0.9 g/kg/day. 6. The pharmaceutical composition of claim 5, wherein in the compound of Formula IV M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH; and wherein in the compound of Formula I, M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5 and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH. 7. The pharmaceutical composition of claim 5, wherein the compound of Formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof, and the compound of Formula I is phenylacetylglutamine or pharmaceutically acceptable salts thereof. 8. A pharmaceutical composition, comprising in aqueous solution (a) a compound of Formula I: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl(C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II: wherein X is a halogen, lower alkyl (C1-6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-12), or hydroxy and n is 0, 1, 2, 3, or 4; and b) a compound of formula III: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl (C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from Formula II; and wherein the compound of Formula IV is present in a 4:1 ratio by weight to the compound of formula III and the combined concentration of the compound of Formula IV and the compound of Formula III is from 70 mg/mL to 150 mg/ml. 9. The pharmaceutical composition of claim 8, wherein in the compound of Formula IV M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH; and wherein in the compound of Formula III M is hydrogen or sodium; n is 0; R is H or C3H7; R1 is selected from the group consisting of H, CH3, CH3-O-, C2H5, and C3H7; R2 is selected from Formula II, wherein X is Cl, F, or OH. 10. The pharmaceutical composition of claim 8, wherein the compound of Formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof, and the compound of Formula III is phenylacetylisoglutamine or pharmaceutically acceptable salts thereof. 11. The pharmaceutical composition of any one of claims 7 or 10, wherein the combined concentration is about 80 mg/mL. 12. A pharmaceutical composition comprising phenylacetylglutamine, phenylacetylisoglutamine and water sufficient to form an aqueous solution in a concentration ranging from about 200 mg/mL to about 350 mg/mL. 13. A method of treating neoplastic disease, comprising: a) administering a pharmaceutical composition of any one of claims 1 to 4 or 12 to a patient at an infusion rate from 100 mL/hr to 400 mL/hr, preferably from 250 mL/hr to 300 mL/hr, wherein the composition is administered at a rate sufficient to reach a dosage level of from 0.6 g/kg/day to 25 g/kg/day, preferably from 5.0 g/kg/day to 12.0 g/kg/day. 14. A method of treating neoplastic disease, comprising: a) administering a pharmaceutical composition of any one of claims 8 to 12 or 15 to 17 to a patient at an infusion rate from 100 mL/hr to 400 mL/hr, preferably from 250 mL/hr to 300 mL/hr, wherein the composition is administered at a rate sufficient to reach a dosage level of from 0.1 g/kg/day to 2.6 g/kg/day, preferably from 0.2 g/kg/day to 0.9 g/kg/day. 15. A pharmaceutical composition, comprising an aqueous solution of a compound of Formula IV: wherein n is 0-5; M is hydrogen, a salt forming cation, an alkyl(C1-6), a cycloalkyl, or an aryl (C6-12); R and R1 are independently selected from the group consisting of H, lower alkoxy (C1-6), and lower alkyl (C1-6); R2 is selected from substituents of Formula II: wherein X is a halogen, lower alkyl (C1-6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl (C6-12), or hydroxy and n is 0, 1, 2, 3, or 4; and wherein the concentration of the compound of Formula IV is from 70 mg/mL to 150 mg/mL. 16. The composition of claim 15, wherein the compound of Formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof. 17. The composition of claim 15, wherein the compound of Formula IV is a precursor compound of phenylacetic acid, preferably phenylbutyric acid or its pharmaceutically acceptable salts thereof.

Description

BACKGROUND OF THE INVENTION

1. The scope of the invention.

The present invention generally relates to the field of treatment of neoplastic diseases. More specifically, it relates to the intravenous administration of highly concentrated solutions of phenylacetylglutamine and phenylacetylisoglutamine or phenylacetylglutamine and phenylacetate or their salts or derivatives with high infusion rates and high doses.

2. Description of the prior art.

Studies of growth factors and growth inhibitors over the past thirty years indicate the possible existence of a protective system in the human body that is complementary to the immune system. This protective system of differentiation inducers and regulators of the expression of oncogenes and tumor suppressor genes can be called a “biochemical protective system” or “ΒΌ8”. While the main goal of the immune system is to protect the body from external invasion, the main goal of ΒΌ8 is to protect the body from defective cells. Human neoplastic diseases (cancers, malignant and benign tumors) are examples of diseases that ΒΌ8 fights against. One group of compounds that provide the ΒΌ8 components are analogues of natural amino acids and carboxylic acids.

Without being bound by theory, the mechanism of protection against cancer using analogues of natural amino acids can be the induction of differentiation, conjugation of glutamine to inhibit the growth of tumor cells, downregulation of oncogenes such as the pelvis, or upregulation of detoxification genes such as C8TP1 and C8TM1 and tumor suppressor genes such as p53, the retinoblastoma gene, and type 1 neurofibromatosis gene, possibly due to a decrease in methylation of hypermethylated genes. Regardless of the detailed mechanism of action, it is known that analogues of natural amino acids induce abnormal cells to undergo final differentiation and die as a result of programmed cell death. Unlike necrosis associated with chemotherapy or radiation therapy, dead cells are gradually removed and replaced by normal cells, leading to healing of the organ and restoration of function.

The study of analogues of natural amino acids as potential antitumor agents, hereinafter mainly “antineoplastons”, began in 1967 with the observation of a significant deficit in the content of serum peptides in patients with cancer. During the 80s ΒιΐΓζν pzk | reported the isolation of antineoplaston fractions from human urine and the use of these fractions for the treatment of human cancer, U.S. Patent 4,470,970, the entire disclosure of which is incorporated by reference. Among the compositions presented for the treatment of cancer were a) 3-phenylacetylamino-2,6-piperidinedione and b) a mixture of sodium phenylacetate and phenylacetylglutamine in a ratio of 4: 1 by weight. Composition (b) refers hereinafter to “antineoplaston A82-1” or simply “A82-1”. It was found that 3-phenylacetylamino-2,6-piperidinedione is hydrolyzed by sodium hydroxide upon dissolution and neutralization into phenylacetylglutamine and phenylacetylisoglutamine in a ratio of 4: 1.

Dosage forms of the above compositions were prepared and they showed good activity in preclinical trials. 3-Phenylacetylamino-2,6-piperidinedione has a cytostatic effect in cultured human mammary tumor cells of the ΜΌΑ-ΜΒ-231 line. Dose-dependent inhibition of the growth curves of cell lines KMSN-1, S-1 and S-1, rat lymphoma IIb and human colon adenocarcinoma with the use of 3-phenylacetylamino-2,6-piperidinedione was also observed.

Ίη νίνο experiments were carried out in which 3-phenylacetylamino-2,6-piperidinedione or A10 was administered to mice implanted with 8180 cells or P-27 breast tumor cells. In an experiment with 8180, cAMP levels in the liver and tumors of the treated mice were significantly higher compared to control mice after administration of 3-phenylacetylamino

2,6-piperidinedione. In the P-27 experiment, after the injection of A10, inhibition of ³ H-T6P uptake and inhibition of the growth curve were observed.

A82-1 or phenylacetic acid leads to dose-dependent inhibition of the growth of breast carcinoma cells of the ΗΒΕ-100 and Κί-1 line and also contributes to the final differentiation or phenotypic reversal of human promyelocytic leukemia cell lines Hb-60, chronic lymphocytic leukemia, neuroblastoma, murine fibrosarcoma U7T, hormone-resistant PC3 prostate adenocarcinoma, astrocytoma, medulloblastoma, malignant melanoma and ovarian carcinoma. A82-1 or phenylacetic acid causes an adipocyte transformation in cultured precancerous mesenchymal C3H 10T1 / 2 cells and enhances the production of hemoglobin in erythroleukemic K562 cells. In addition, and unlike the currently available conventional chemotherapeutic drugs, such as 5-aza-2-deoxycytidine, phenylacetic acid does not cause tumor progression in precancerous C3H 10T1 / 2 cells.

In preclinical toxicological studies, it was found that LI ₅₀ A10 in mice is 10.33 g / kg / day.

At the autopsy of dead animals, generalized congestion in the internal organs, pulmonary edema, and hemorrhagic changes in the alveoli were revealed. At autopsy, the surviving experimental animals were identical to the control animals. In experiments on chronic toxicity, no adverse effects were detected after 180 days.

1.1), A82-1 in mice was 2.33 g / kg / day. An autopsy of dead animals revealed generalized congestion in the internal organs, pulmonary edema and hemorrhagic changes in the alveoli, as well as Tadeu spots and congestion in the thymus. In experiments on chronic toxicity when administered to a dose of 1.11 g / kg / day, no adverse effects were detected after 365 days.

It was found that A10 and A82-1 are not mutagens in the Ames test and A10 does not have teratogenic effects against rat fetuses.

A noteworthy issue regarding toxicological studies is that phenylacetylglutamine, component A82-1, and also the decomposition product of 3 phenylacetylamino-2,6-piperidinedione, are not usually found in mice, but are usually found in humans. Based on this, it can be assumed that humans may show greater resistance to both A10 and A82-1 than mice, and thus, large doses of both compositions are possible for humans. This assumption was correct, as will be shown below.

In toxicological studies in humans in Phase I clinical trials, intravenous administration of A10 at doses up to 2.21 g / kg / day was associated with minimal side effects, including fever, muscle and joint pain, muscle contractions in the throat, and pain in the abdomen short duration and isolated cases of nausea, dizziness and headache (Aegis /, Exp11. C11i. Be8., 1986, 12 8irr1.1, 47-55).

Oral administration of A82-1 in doses up to 238 mg / kg / day was associated with a temporary slight decrease in the number of leukocytes in one patient. Injection administration of A82-1 in doses up to 160 mg / kg / day was associated with minimal side effects, including slight nausea and vomiting, a skin allergic reaction, a moderate increase in blood pressure, fever, a slight decrease in the number of leukocytes (in each case in one patient ) and a slight imbalance in electrolytes in three patients.

In clinical experiments, it was found that 3-phenylacetylamino-2,6-piperidinedione,

A10 and A82-1 were effective in treating cancer.

ΒιΐΓζνηδΚί e! a1. (Igidk Ehrb. Syp.Vek., 1986, 12

8irr 1. 1, 25-35 (1986)) reported that an A82-1 antineoplaston solution for intravenous injection (100 mg / ml of active ingredients) was administered to patients in doses of not more than 0.16 g / kg / day. Of the 21 cases of neoplastic disease, six complete remissions, two partial remissions, seven stabilization and six cases of disease progression were observed.

A phase II clinical trial was conducted in which patients with astrocytoma were given A10 (100 mg / ml) in doses of 0.5 to 1.3 g / kg / day or A82-1 (100 mg / ml) in doses of 0.2 to 0.5 g / kg / day for 67-706 days (in: Peset Abuapsek ίη Syeto1yegaru. Abat. Ό., Eb. Mishsy: Ei1igateb, 1992). Of the 20 patients, four had a complete response, two had a partial response, ten had stabilization, and four had disease progression.

U 8at1b, US Pat. No. 5,605,930 (the entire contents of which is incorporated by reference), sodium phenylacetate alone was used to treat human cancer and was administered in doses of not more than 0.3 g / kg / day. However, disadvantages were observed at low concentrations, flow rates and doses of solutions for intravenous administration.

First off e! a1. (Egidk Exp.C1sh.Be8., 12 8irr1. 1, 11-16 (1986)) reported a complete reduction in the colonies of tumor cells of the HBB-100 and Κί Νο 1 lines under the action of 5.0 mg / ml or phenylacetic acid or antineoplaston A82-1. Similarly, cytostasis of human tumor cells of breast carcinoma of the MEA-MB-231 line was observed using concentrations of 3-phenylacetylamino-2,6-piperidinedione 2.0 mg / ml and A82-1 3.0 mg / ml. However 3-phenylacetylamino

2.6-piperidinedione is slightly soluble in water, and when administered to rats by mouth, the maximum plasma level is approximately 0.2 mg / ml, roughly 10 times lower than the cytostatic concentration observed in experiments with tissue cultures. With the usual administration schemes of antineoplaston A82-1, the maximum plasma concentrations of phenylacetic acid are approximately 0.43 mg / ml, roughly 7 times lower than the cytostatic concentration observed in experiments with tissue cultures. In addition, like 3-phenylacetylamino

2.6- piperidinedione, the products of its hydrolysis and A82-1 are rapidly released ίη νίνο.

Also, when antineoplastons are absorbed by the tumor tissue, a concentration gradient is formed between the outside of the tumor tissue, in which the concentration of antineoplaston will be equal to the concentration in the blood plasma, and the point or points inside the tumor tissue, in which the concentration of antineoplaston will be minimal and may be zero. Therefore, relatively low concentrations of antitumor agents in the plasma lead to the fact that in some internal part of the tumor tissue there is no significant absorption of the antitumor agent, and it remains in its tumor state.

Second, the introduction of a solution including the hydrolysis products of 3-phenylacetylamino-2,6 piperidinedione, with low infusion rates from 2.5 ml / h to 84 ml / h, often leads to an increase in the level of plasma products of excretion. An example of an excretory product of such a cleavage is uric acid. This increase interferes with treatment, leading to the need to either reduce the dose or interrupt treatment to administer additional drugs, such as allopurinol, to lower the level of excretory product, such as uric acid.

Therefore, it is desirable to have dosage forms for intravenous administration of antitumor activity amino acid analog compositions, wherein the intravenous dosage forms provide high plasma concentrations of the active ingredient or ingredients to fully penetrate into the tumor effective amounts of the active ingredient or ingredients. It is also desirable that such dosage forms for intravenous administration do not lead to elevated levels of plasma excretion products.

SUMMARY OF THE INVENTION

The present invention relates to a method for treating a neoplastic disease, including cancer, comprising administering to a patient a pharmaceutical composition comprising phenylacetylglutamine of formula I and phenylacetylisoglutamine of formula III. The compound of formula I is in a 4: 1 ratio by weight to the phenylacetylisoglutamine of formula III.

Formula I is represented by the structure

where K. and K _| independently selected from the group consisting of H, lower alkoxy (C _1-6 ) or lower alkyl (C _1-6 ); K ₂ is selected from the group consisting of aryl (C _6-12 ); M is hydrogen, salt forming cation such as sodium, potassium or ammonium, lower alkyl (C 1 -C _6), cycloalkyl, or aryl (C _6-12), and η is equal to 05. Preferably M is hydrogen, salt forming cation, alkyl (C _1-6 ), cycloalkyl or aryl (C _6-12 ). More preferably, M is hydrogen or sodium; η is 0; K is selected from the group consisting of H and C ₃ H ₇ ; To _| selected from the group consisting of H, CH ₃ , CH ₃ —O—, C ₂ H ₅ and C ₃ H ₇ ; K ₂ is an aryl selected from the group consisting of formula II:

Formula II

where X is halogen, lower alkyl (C _1-6 ), lower alkoxy (C _1-6 ), cycloalkyl, cycloalkoxy, aryl (C _6-12 ), or hydroxy, and η is 0, 1, 2, 3 or 4 More preferably, K ₂ is phenyl or is selected from the group of formula II, wherein X is selected from C1, B or OH. Most preferably, K ₂ is phenyl or phenyl chloride. In addition, the compound of formula I can be used as a racemic mixture or as individual optical isomers or any combination thereof.

Formula III is represented by the structure:

where K and K are independently selected from the group consisting of H, lower alkoxy (C _1-6 ) or lower alkyl (C _1-6 ); K ₂ is selected from the group consisting of aryl (C _6-12 ); M is hydrogen, forming a salt with a cation, such as sodium, potassium or ammonium, diethanolamine, cyclohexylamine, a natural amino acid with a molecular weight of less than 500 KO, lower alkyl (C _1-6 ), cycloalkyl or aryl (C _6-12 ), and η is 0-5. Preferably M is hydrogen or sodium; η is 0; K is selected from the group consisting of H and C3H7; K1 is selected from the group consisting of H, CH3, CH ₃ —O—, C ₂ H ₅ and C ₃ H ₇ ; K ₂ is aryl (C _6-12 ) selected from the group consisting of formula II, where X is halogen, lower alkyl (C _1-6 ), lower alkoxy (C _1-6 ), cycloalkyl, cycloalkoxy, aryl (C6 -12) substituted with aryl or hydroxy, and η is 0, 1, 2, 3, or 4. More preferably, K ₂ is phenyl of formula II, wherein X is selected from C1, B or OH. Most preferably, K ₂ is phenyl or phenyl chloride. In the same way, a compound of formula III can be used as a racemic mixture or as individual optical isomers or any combination thereof.

In the composition, the combined concentration of phenylacetylglutamine of formula I and phenylacetylisoglutamine of formula III in an aqueous solution is from 200 mg / ml to 350 mg / ml, and the composition is administered at an infusion rate of from 2.5 ml / h to 400 ml / h, preferably from 100 ml / h up to 400 ml / h.

In a further embodiment, the present invention relates to a method for treating a neoplastic disease, including cancer, comprising administering a pharmaceutical composition, a pharmaceutical composition comprising phenylacetic acid of the formula

IV:

Formula IV

Η

where K and Κι are independently selected from the group consisting of H, lower alkoxy (C _1-6 ) or lower alkyl (C _1-6 ); K ₂ is selected from the group consisting of aryl (C _6-12 ); M is hydrogen, salt forming cation such as sodium, potassium or ammonium, lower alkyl (C 1 -C _6), cycloalkyl, or aryl (C _6-12), and η is equal to 05. Preferably M is hydrogen or sodium; η is 0; K is selected from the group consisting of H and C ₃ H ₇ ; K ₁ is selected from the group consisting of H, CH ₃ , CH ₃ —O—, C ₂ H ₅ and C ₃ H ₇ ; K ₂ is an aryl selected from the group consisting of formula II, where X is halogen, lower alkyl (C _1-6 ), lower alkoxy (C _1-6 ), cycloalkyl, cycloalkoxy, aryl (C ₆₁₂ ), or hydroxy, and η is 0, 1, 2, 3, or 4. More preferably, K ₂ is phenyl selected from the group of formula II, wherein X is selected from C1, B, or OH. Most preferably, K ₂ is phenyl or phenyl chloride.

In another embodiment, the compound of formula IV is present in a 4: 1 ratio by weight to the compound of formula I, usually in an aqueous solution. In the composition, the combined concentration of the compound of formula I and the compound of formula IV is from 70 mg / ml to 150 mg / ml, and the composition is administered at an infusion rate of from 2.5 to 400 ml / h, preferably from 100 to 400 ml / h.

In yet another embodiment, the present invention relates to a pharmaceutical composition comprising a 4: 1 compound of formula IV to a compound of formula III, wherein the combined concentration of a compound of formula IV and a compound of formula III is from 200 to 350 mg / ml, and the composition is administered at an infusion rate 2.5 to 400 ml / h, preferably 100 to 400 ml / h.

These flow rates are significantly higher than any known previously reported for antitumor drugs. High flow rates are useful in the treatment of cancer, since they can achieve roughly two times higher concentrations of antineoplaston A10 active agents in the blood than with normal, lower infusion rates. High flow rates make it possible to achieve blood concentrations comparable to those that have been shown to exhibit antitumor activity in tissue culture and also to achieve higher penetration into tumor tissue. Therefore, high flow rates are more effective than lower flow rates in the treatment of cancer.

Description of illustrative embodiments

In the description of the invention, the term "antineoplaston A10" is defined as a mixture of sodium salts of phenylacetylglutamine and phenylacetylisoglutamine in a ratio of 4: 1.

The terms "antineoplaston L82-1" and "L821" are defined as a mixture of sodium salts of phenylacetic acid and phenylacetylglutamine in a ratio of 4: 1.

The term "patient" includes people and patients in veterinary medicine.

The invention describes preferred embodiments known at the time of filing of this application, representing the best method that can be expected at present to implement and use the pharmaceutical compositions of the present invention in the methods of the present invention.

A. Preparation of pharmaceutical compositions.

The pharmaceutical compositions of the present invention include, in one embodiment, a compound of formula I:

Formula I

where K and Κι are independently selected from the group consisting of H, lower alkoxy (C _1-6 ) or lower alkyl (C _1-6 ); K ₂ is selected from the group consisting of aryl (C _6-12 ) and substituted aryl; M is hydrogen, forming a salt with a cation, such as sodium, potassium or ammonium, alkyl (C _1-6 ), cycloalkyl or aryl (C _6-12 ), and η is 0-5. Preferably M is hydrogen or sodium; η is 0; K is selected from the group consisting of H and C3H7; K1 is selected from the group consisting of H, CH3, CH3-O-, C2H5 and C3H7; K2 is aryl (C6-12) selected from the group consisting of formula II:

where X is halogen, lower alkyl (C1-6), lower alkoxy (C1-6), cycloalkyl, cycloalkoxy, aryl ( _C6-12 ) or hydroxy, and η is 0, 1, 2, 3 or 4. More preferably K2 is phenyl selected from the group of formula II, wherein X is selected from C1, B or OH. Most preferably, K ₂ is phenyl or phenyl chloride.

The compound of formula I is in a ratio of 4: 1 by weight to the compound of formula III:

Formula III

where K and K] are independently selected from the group consisting of H, lower alkoxy (C _1-6 ) or lower alkyl (C _1-6 ); K ₂ is selected from the group consisting of aryl (C _6-12 ); M is hydrogen, forming a salt with a cation, such as sodium, potassium or ammonium, alkyl (C _1-6 ), cycloalkyl or aryl (C _6-12 ), and η is 0-5. Preferably M is hydrogen or sodium; η is 0; K is selected from the group consisting of H and C ₃ H ₇ ; K ₁ is selected from the group consisting of H, CH ₃ , CH ₃ —O—, C ₂ H ₅ and C ₃ H ₇ ; K ₂ is an aryl selected from the group consisting of formula II, where X is halogen, lower alkyl (C _1-6 ), lower alkoxy (C _1-6 ), cycloalkyl, cycloalkoxy, aryl (C _6-12 ) or hydroxy and η is 0, 1, 2, 3, or 4. More preferably, K ₂ is phenyl selected from the group of formula II, wherein X is selected from C1, P or OH. Most preferably, K ₂ is phenyl or phenyl chloride.

In the composition, the combined concentration of the compound of formula I and the compound of formula III is from 200 to 350 mg / ml. In a preferred aspect of this embodiment of the invention, the compound of formula I is phenylacetylglutamine or its pharmaceutically acceptable salts, and the compound of formula III is phenylacetylisoglutamine or its pharmaceutically acceptable salts, and the combined concentration of the compound of formula I and the compound of formula III is 300 mg / ml. Typically, a racemic mixture of each compound will be used, however, individual optical isomers can also be used.

In a second embodiment, the pharmaceutical compositions of the present invention comprise an aqueous solution of a compound of formula IV:

Formula IV

where K and K are independently selected from the group consisting of H, lower alkoxy (C _1-6 ) or lower alkyl (C _1-6 ); K ₂ is selected from the group consisting of aryl (C _6-12 ); M is hydrogen, forming a salt with a cation, such as sodium, potassium or ammonium, alkyl (C _1-6 ), cycloalkyl or aryl (C _6-12 ), and η is 0-5. Preferably M is hydrogen or sodium; η is 0; K is selected from the group consisting of H and C ₃ H ₇ ; K ₁ is selected from the group consisting of H, CH ₃ , CH ₃ —O—, C ₂ H ₅ and C ₃ H ₇ ; K ₂ is an aryl selected from the group consisting of formula II, where X is halogen, lower alkyl (C _1-6 ), lower alkoxy (C _1-6 ), cycloalkyl, cycloalkoxy, aryl (C6-12) or hydroxy and η is 0, 1, 2, 3, or 4. More preferably, K ₂ is phenyl selected from the group of formula II, wherein X is selected from C1, P or OH. Most preferably, K ₂ is phenyl or phenyl chloride.

The compound of formula IV is in a 4: 1 ratio by weight to the compound of formula I, and in the composition, the combined concentration of the compound of formula I and the compound of formula IV is from 70 to 150 mg / ml.

One embodiment of this aspect of the invention involves administering pharmaceutical compositions comprising compounds of formula IV and formula I at an infusion rate of from 100 to 400 ml / h. In a preferred aspect of this embodiment of the invention, the pharmaceutical compositions are administered at an infusion rate of from 250 to 300 ml / h, for the most part sufficient to achieve a dose of from 0.1 to 2.6 g / kg / day. In an even more preferred embodiment, the pharmaceutical composition is administered at a rate of from 250 to 300 ml / h, for the most part sufficient to achieve a dose of from 0.2 to 0.9 g / kg / day.

In a preferred aspect of this embodiment of the invention, the compound of formula IV is phenylacetic acid or its pharmaceutically acceptable salts, and the compound of formula I is phenylacetylglutamine or its pharmaceutically acceptable salts, and the combined concentrations of the compound of formula IV and the compound of formula I are 80 mg / ml.

In another embodiment of the invention, the compound of formula IV is in a 4: 1 ratio by weight to the compound of formula III, and in the composition, the combined concentration of the compound of formula IV and the compound of formula III is from 70 to 150 mg / ml.

In a preferred aspect of this embodiment of the invention, the compound of formula IV is phenylacetic acid or its pharmaceutically acceptable salts, and the compound of formula III is phenylacetylisoglutamine or its pharmaceutically acceptable salts, and the combined concentration of the compound of formula IV and the compound of formula III is 80 mg / ml.

In further embodiments of the present invention, the pharmaceutical composition comprises a solution of either a compound of formula I or a compound of formula III. In one aspect of this embodiment of the invention, the pharmaceutical composition comprises phenylacetylglutamine or a pharmaceutically acceptable salt thereof in solution at a concentration of 200 to 350 mg / ml. In another aspect of this embodiment of the invention, the pharmaceutical composition comprises phenylacetylisoglutamine or a pharmaceutically acceptable salt thereof in solution in a concentration of 200 to 350 mg / ml. In particularly preferred aspects of these embodiments of the present invention, the solutions are aqueous solutions.

In other embodiments of the present invention, the pharmaceutical composition comprises an aqueous solution of a compound of formula IV, wherein the compound of formula IV is in a concentration of from 70 to 150 mg / ml. In one aspect of this embodiment of the invention, the compound of formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof. In another aspect of this embodiment, the compound of formula IV is a precursor of phenylacetic acid, such as phenylbutyric acid or its pharmaceutically acceptable salts.

Preferred compounds of formula I are phenylacetylglutamine and the phenylacetylglutamine sodium salt and its optical isomers; formula III, phenylacetylisoglutamine and phenylacetylisoglutamine sodium salt; and formula IV, phenylacetic acid and sodium phenylacetate.

Phenylacetylglutamine can be isolated from human body fluids, such as urine, or can be synthesized by methods known in the art, for example by treating Ν, Ν'-disuccinimidyl carbonate in acetonitrile with subsequent interaction with b-glutamine in the presence of №1CO ₃ . in a mixture of acetonitrile / water 1: 1. Phenylacetylglutamine can also be synthesized by reacting phenylacetyl chloride with L-glutamine in the presence of NaHCO ₃ in an aqueous solution. Another synthesis method that can be used is the treatment of 3-phenylacetylamino-2,6-piperidinedione with sodium hydroxide.

Phenylacetylisoglutamine can be synthesized by reacting phenylacetyl chloride with Lglutamine to form phenylacetylglutamine, followed by heating in vacuo at 160 ° C to give 3-phenylacetylamino

2,6-piperidinedione, which can then be treated with sodium hydroxide. Phenylacetylisoglutamine can also be obtained by treating phenylacetic acid with Ν, Ν'-disuccinimidyl carbonate in acetonitrile, followed by reaction with b-isoglutamine in the presence of ΝαΗί.Ό ₃ in a 1: 1 acetonitrile / water mixture. However, for the second synthesis, isoglutamine is necessary, which is expensive, so the first route is preferable for economic reasons.

Phenylacetic acid can be isolated from body fluids, such as urine, or it can be synthesized by methods known in the art, such as refluxing benzyl cyanide with dilute sulfuric or hydrochloric acid.

Other compounds of formulas I, III, and IV can be synthesized by methods known in the art. For example, acid addition salts can be prepared from free base compounds by reacting the latter with one equivalent of a suitable, non-toxic, pharmaceutically acceptable acid, followed by distilling off the solvent used for the reaction and, if necessary, recrystallizing the salt. The free base can be obtained from an acid addition salt by reacting the salt with an aqueous salt solution with a suitable base such as sodium carbonate, sodium hydroxide and the like.

"Pharmaceutically acceptable salts" means salts having the biological activity of the parent compound and losing their toxic activity at the chosen level of administration. In addition, it can be determined whether the salt is pharmaceutically acceptable by methods known to those skilled in the art. Pharmaceutically acceptable salts of phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid include, but are not limited to, inorganic salts of sodium, potassium and ammonium, and organic salts of diethanolamine, cyclohexylamine and amino acids. Preferably, the salt is a sodium salt.

Suitable acids for preparing acid addition salts for the compounds of the present invention include, but are not limited to, acetic, benzoic, benzenesulfonic, tartaric, hydrobromic, hydrochloric, citric, fumaric, gluconic, glucuronic, glutamic, lactic, malic, maleic, methanesulfonic, salicylic, stearic, succinic, sulfuric and tartaric acids. The group of acids suitable for the formation of non-toxic, pharmaceutically acceptable salts is well known to practitioners in the field of pharmaceutical compositions (see, for example, 81 series E. Vegde, s1 a1., 1.Pag. 8c1eise8, 66: 1-19 (1977)).

The compounds of the present invention can also exist in various stereoisomeric forms due to the presence of one or more asymmetric centers in the compound. The present invention includes all stereoisomeric forms of the compounds, as well as mixtures thereof, including racemic mixtures. If desired, individual stereoisomers can be prepared by methods known in the art, for example by resolving the stereoisomers on chiral chromatographic columns.

In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.

Precursors of phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid may be used in the present compositions. Precursors of phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid are defined as compounds that can be metabolized to form phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid in humans. Pharmaceutically acceptable precursors of phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid are precursors that lose their toxic activity at the chosen level of administration, either alone or as any intermediate metabolism between the precursor and the final product. To determine which precursors of phenylacetylglutamine, phenylacetylisoglutamine and phenylacetic acid are pharmaceutically acceptable, using methods known to specialists in this field. A preferred precursor of phenylacetylglutamine and phenylacetylisoglutamine is 3-phenylacetylamino-2,6 piperidinedione. A preferred phenylacetic acid precursor for use in the present invention is phenylbutyrate, the structure of which is as follows:

For compounds of formulas I, III, and IV, post-synthesis may require purification. Any known methods can be used to separate the desired compound from other compounds or impurities, for example, among others, HPLC and crystallization from water. Compounds can be quantified by any known method.

To prepare the pharmaceutical composition of antineoplaston A10, an aqueous solution of the phenylacetylglutamine sodium salt and the phenylacetylisoglutamine sodium salt in a ratio of 4: 1 is prepared so that the concentration of phenylacetylglutamine in the solution is between 160 and 280 mg / ml and preferably between 230 and 250 mg / ml, and the concentration phenylacetylisoglutamine in solution is between 40 and 70 mg / ml, and preferably between 55 and 65 mg / ml. The preparation of the solution can be carried out using any method known to specialists in this field. It should be noted that the solution must be prepared sterile, and the pH is adjusted to a value equal to or close to the pH of the blood plasma

7.4, for example, pH 7.0. The active ingredients, if desired, can be obtained, like any compounds of formulas I and III, before preparing the solution.

To prepare the pharmaceutical composition of antineoplastone A82-1 of the present invention, an aqueous solution of sodium phenylacetate and phenylacetylglutamine sodium salt is prepared in a ratio of 4: 1 by weight such that the phenylacetate concentration is between 56 and 120 mg / ml and preferably between 62 and 66 mg / ml; and the phenylacetylglutamine concentration is between 14 and 30 mg / ml, and preferably between 15 and 17 mg / ml. The preparation of the solution can be carried out using any method known to specialists in this field. It should be noted that the solution must be prepared sterile, and the pH is adjusted to a value equal to or close to the physiological pH of 7.4, for example, pH 7.0. Active ingredients can be obtained, like any compounds of formulas IV and I, before preparing the solution, if such use is desired.

Both for antineoplaston A10 and antineoplaston A82-1, the concentration of active ingredients used is significantly higher than those used for any known, previously reported, aqueous solutions of antitumor drug compositions.

Optionally, all compositions of the present invention may include other agents, such as a buffering agent, glucose, other sugars, preservatives, etc., suitable for use in pharmaceutical compositions for intravenous administration, which are known in this field.

B. Introduction of pharmaceutical compositions.

The pharmaceutical compositions of the present invention are administered intravenously. Intravenous administration methods are widely known in the art.

One embodiment of the present invention includes the administration of pharmaceutical compositions comprising compounds of formula I and formula III in a 4: 1 ratio with an infusion rate of from 100 to 400 ml / h. In this embodiment of the invention, the combined concentration of the compound of formula I and the compound of formula III is from 200 to 350 mg / ml.

In the present invention, the flow rate during intravenous infusion of antineoplaston A10 may be between 2.5 and 400 ml / h for administration to adults and young children. Preferably, the intravenous flow rate is from 100 to 400 ml / h. Typical flow rates are 250 ml / h for adults and 100-250 ml / h for young children; flow rates are usually higher for older children.

These flow rates are significantly higher than any known previously reported for antitumor drugs. High flow rates are useful in the treatment of cancer, since they allow the concentration of antineoplaston A10 active agents in the blood to be roughly twice as high as with conventional lower flow rates. High flow rates make it possible to achieve blood concentrations that are comparable to those that have been shown to have antitumor activity in tissue culture and also to achieve higher penetration into tumor tissue. Therefore, in the treatment of cancer, high flow rates are more effective than lower infusion rates.

The high flow rate during the infusion of antineoplaston A10 and the high concentration of antineoplaston A10 cause a diuretic effect. The diuretic effect is useful for the patient in order to prevent fluid overload as a result of large volumes for infusion. The diuretic effect is also useful for the patient in providing a mechanism for removing excretion products that might otherwise accumulate in the body.

The antineoplaston A10 composition of the present invention can be administered at a high flow rate of the present invention one or more than once a day, for example 4 to 12 times a day for a period of time between 15 minutes and 24 hours. A typical administration schedule is 6- 8 infusions / day, each infusion lasting from about 90 minutes to 120 minutes.

In the case of a hypersensitivity reaction (usually expressed as skin rashes) in patients with antineoplaston A10, the desensitization protocol can be followed. The total daily dose is administered in 96 injections (i.e., every 15 minutes) at a flow rate of ml / min - 4 ml / min (240 ml / h).

The daily dose of antineoplaston A10 may be between 0.6 and 25 g / kg / day. Preferably, the daily dose of antineoplaston A10 is between 5.0 and 12.0 g / kg / day. Typically, the daily dose of antineoplaston A10 is approximately 8.0 g / kg / day.

One embodiment of the present invention includes the administration of pharmaceutical compositions comprising compounds of formula IV and formula III in a 4: 1 ratio with an infusion rate of from 100 to 400 ml / h. In this embodiment of the invention, the combined concentration of the compound of formula IV and the compound of formula III is from 70 to 150 mg / ml. In a preferred aspect of this embodiment of the invention, the pharmaceutical compositions are administered at an infusion rate of from 250 to 300 ml / h, for the most part sufficient to achieve a dose of 0.1 to 2.6 g / kg / day. In an even more preferred embodiment, the pharmaceutical composition is administered at a rate of from 250 to 300 ml / h, in most cases sufficient to achieve a dose of 0.2-0.9 g / kg / day.

The present invention is also directed to the intravenous infusion of antineoplaston A82-1. The flow rate during intravenous infusion of antineoplaston A82-1 may be in the range between 2.5 and 400 ml / h when administered to adults and may vary between 25 and 400 ml / h when administered to small children. Preferably, the intravenous flow rate is from 100 to 400 ml / h for adults and young children. Typical flow rates are 250 ml / h for adults and 100,250 ml / h for young children; flow rates are usually higher for older children.

These flow rates are significantly higher than any known previously reported for antitumor drugs. High flow rates are useful in the treatment of cancer, since they allow the concentration of antineoplaston A82-1 active agents in the blood to be roughly twice as high as with conventional, lower infusion rates. As described above, high flow rates make it possible to achieve blood concentrations that are comparable to those that have been shown to have antitumor activity in tissue culture and also to achieve higher penetration into tumor tissue.

The high flow rate during the infusion of antineoplaston A 82-1 and a high concentration of antineoplaston A 82-1 cause a diuretic effect. The diuretic effect is useful for the patient in order to prevent fluid overload as a result of large volumes for infusion and to provide a mechanism for the removal of excretion products that might otherwise accumulate in the body, as described above.

The antineoplaston A82-1 composition of the present invention can be administered at a high rate according to the present invention once or more than once a day, for example 4 to 12 times a day for a period of time between 5 minutes and 24 hours. A typical administration schedule is 6- 8 infusions / day, each infusion lasting from about 10 to 120 minutes.

In the case of a hypersensitivity reaction (usually expressed as skin rashes) in patients with A82-1, the desensitization protocol can be followed. The total daily dose is administered in 96 injections (i.e., every 15 minutes) at a flow rate of 1 ml / min - 4 ml / min (240 ml / h).

The daily dose of antineoplaston A82-1 may be between 0.1 and 2.6 g / kg / day. Preferably, the daily dose of antineoplaston

A82-1 is between 0.2 and 0.9 g / kg / day. Typically, the daily dose of antineoplaston A82-1 is approximately 0.4 g / kg / day.

Another embodiment of the invention includes the treatment of a neoplastic disease with the introduction of two pharmaceutical compositions. According to this embodiment, the first pharmaceutical composition includes an aqueous solution of a compound of formula I and a compound of formula III in a 4: 1 ratio by weight. The combined concentration of the compound of formula I and the compound of formula III in the first pharmaceutical composition is 200 to 350 mg / ml, and the first pharmaceutical composition is administered at an infusion rate of 100 to 400 ml / g.

The second pharmaceutical composition includes an aqueous solution of a compound of formula IV and a compound of formula I, in a ratio of 4: 1 by weight. Alternatively, the second pharmaceutical composition comprises an aqueous solution of a compound of formula IV and a compound of formula III. The combined concentration of the compound of formula IV and the compound of formula I (or formula III) in the second pharmaceutical composition is from 70 to 150 mg / ml, and the second pharmaceutical composition is administered at an infusion rate of from 100 to 400 ml / h.

In a preferred aspect of this embodiment of the invention, the first and second pharmaceutical compositions are administered at an infusion rate of 250 to 300 ml / h, for the most part sufficient to achieve a dose of 0.6 to 25 g / kg / day for the first pharmaceutical composition and 0.1 to 2.6 g / kg / day for a second pharmaceutical composition. In another preferred aspect of this embodiment of the invention, the first and second pharmaceutical compositions are administered at an infusion rate of 250 to 300 ml / h, mostly sufficient to achieve a dose of 5.0 to 12.0 g / kg / day for the first pharmaceutical composition and 0.2 to 0 9 g / kg / day for a second pharmaceutical composition.

Another embodiment of the invention provides a method of treating a neoplastic disease. This method comprises administering to a patient at an infusion rate of from 100 to 400 ml / h a pharmaceutical composition which comprises an aqueous solution of a compound of formula IV, wherein the compound of formula IV is in a concentration of from 70 to 150 mg / ml.

In one aspect of this embodiment of the invention, the pharmaceutical composition is administered at a rate of from 250 to 300 ml / h, for the most part sufficient to achieve a dose of from 0.1 to 2.6 g / kg / day. In another aspect of this embodiment of the invention, the pharmaceutical composition is administered at a rate of from 250 to 300 ml / h, for the most part sufficient to achieve a dose of from 0.2 to 0.9 g / kg / day. In yet another aspect, the compound of formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof. The compound of formula IV may also be a precursor of phenylacetic acid, such as phenylbutyric acid or its pharmaceutically acceptable salts.

The treatment regimen described above is suitable for treating patients suffering from all types of neoplastic diseases, including cancer of both hard and soft tissues, and malignant and benign tumors. In particular, neoplastic diseases that are predominantly sensitive to treatment using the disclosed treatment regimen of this invention include adrenal carcinoma, bladder carcinoma, breast carcinoma, advanced stage glioma, polymorphic glioblastoma, astrocytoma, including anaplastic and early stage astrocytoma, stem glioma brain, primitive neuroectodermal tumors, including medulloblastoma and pinealoblastoma, rhabdoid tumor of the central nervous system, oligodendroglioma, mixed glioma, neurofibroma, schwanny, optic glioma, ependymoma, germ cell tumors, meningioma, colorectal carcinoma, esophageal carcinoma, primary and metastatic liver cancer, head and neck carcinoma, pulmonary adenocarcinoma, large-cell non-differentiated pulmonary carcinoma, lung carcinoma squamous cell carcinoma of the lung, non-small cell carcinoma of the lung, non-Hodgkin's lymphoma, chronic leukemia, mesothelioma, malignant melanoma, malignant fibrous histiocyte th, multiple myeloma, neuroblastoma, neuroendocrine tumors, ovarian carcinoma, carcinoma of the pancreas, primitive neuroectodermal tumors outside the central nervous system, adenocarcinoma of the prostate, carcinoma of the kidney, sarcomas, carcinoma of the small intestine, gastric carcinoma, carcinoma of the uterus, carcinoma of the vulva, and carcinoma of unknown origin.

The following examples are included to demonstrate preferred embodiments of the invention. Those skilled in the art will appreciate that the methods disclosed in the examples that follow represent the methods disclosed by the inventor for good functioning in the practice of the invention and, therefore, can be considered as preferred methods for their application in practice. However, specialists in this field in the light of the present disclosure will understand that you can make many changes to specific embodiments that are disclosed, and still get a similar and the same result without departing from the invention.

Example 1. Forty-three patients with a diagnosis of primary malignant brain tumors were treated with daily intravenous administration of antineoplaston A10 at an average dose of 7.9 g / kg / day and antineoplaston Ά82-1 at an average dose of 0.39 g / kg / day. Of the 43 patients, 36 were evaluated, and 16 achieved a complete or partial response at the end of therapy without serious side effects.

In all forty-three patients, except one, the diagnosis of the primary brain tumor was histologically confirmed. The remaining patient suffered from a primary brain tumor in the brain stem, from where it was impossible to take a biopsy sample without adequate safety. Fourteen patients were diagnosed with polymorphic glioblastoma, and six patients were diagnosed with anaplastic astrocytoma.

Patients were between 2 years old and 71 years old. Patients were selected according to the Karnofsky index value from 40 to 100, the probability of survival for two months and the age of more than 1 year. Patients with liver failure, with inadequate adequate regulation of hypertension, or pregnant or breast-feeding women, were excluded. All patients had previously undergone surgery or chemotherapy and / or radiation therapy with a negative result.

The antineoplaston A10 composition was prepared as described above with 230-250 mg / ml phenylacetylglutamine and 55-65 mg / ml phenylacetylisoglutamine and adjusted to pH 7.0.

The antineoplaston A82-1 composition was prepared as described above with 62–66 mg / ml sodium phenylacetate and 15–17 mg / ml phenylacetylglutamine and adjusted to pH 7.0.

Patients received intravenous injections of antineoplastons with the help of a single-cavity subclavian catheter (Vgou1ae, Cg51jupd or equivalent). Patients received gradually increasing doses with multiple intermittent injections using a portable, dual-channel programmable pump, Alloy Run 6000 six times a day. Infusion rates for adults were 250 ml / h and for people under 18 years of age, the infusion rates were 50-100 ml / h, depending on tolerance. The infusion was carried out in periods of time from 91 days to 3509 days with an average treatment duration of 661 days. The average dose of A10 was 7.91 g / kg / day, and the average dose of A82-1 was 0.39 g / kg / day. The maximum total dose of antineoplaston A10 was 551.865 kg and the maximum total dose of A82-1 was 59.348 kg.

Before treatment, the evaluated patients fully recovered after surgery, if it was performed, or stopped chemotherapy at least 4 weeks (6 weeks if the chemotherapy consisted of nitrosoureas) and / or stopped radiation therapy at least 6 weeks.

The complete response was evaluated as the complete disappearance of all comparable increasing tumors in studies with viazulation (NMR, etc.) for four weeks or more. The partial response was evaluated as more than 50% reduction in the total product of the largest perpendicular diameters of comparable increasing tumors for at least 4 weeks without the appearance of new lesion sites.

The state of stable disease was estimated as less than 50% change (either increase or decrease) in the total product of the largest perpendicular diameters of comparable increasing tumors for at least 12 weeks. The condition of a progressive disease was estimated as more than 50% increase in the total product of the largest diameters of comparable increasing tumors or the appearance of new lesion sites.

Of the 36 patients evaluated, 7 (19.5%) received a complete response. Nine (25%) patients received a partial response. Stable disease was observed in 12 patients (33.3%). A progressive disease developed in 8 patients (22.2%).

A number of cases of adverse reactions to drugs during the study were noted, including hypernatremia, hypochloremia, hyperchloremia, hypokalemia, skin rashes, drowsiness, weakness, nausea and vomiting, headache, slurred speech, confused consciousness, hallucinations, fever and fluid retention. Most cases of adverse reactions to drugs were weak and did not significantly interrupt the course of treatment. For example, there were 23 cases of hypernatremia with rates no higher than 150 meq / l, twelve cases no higher than 160 meq / l and two cases no higher than 170 meq / l. Hypochloremia was established in six cases and hyperchloremia in two cases. There were seven cases of hypokalemia with rates higher than 2.8 meq / L. The factor limiting the dose of antineoplaston A10 turned out to be the volume of fluid for intravenous administration, and for A82-1 the dose limiting factor was increased drowsiness and weakness.

Of the 16 patients classified as having a complete or partial response, 13 remained alive, as did eight patients with stable disease, progressive disease and not evaluated. Most of the surviving patients are alive and now, four years after the diagnosis of pathology, and two patients, one suffering from oligodendroglioma and one from early stage astrocytoma, live about 12 years from the moment of diagnosis of the pathology.

Therefore, the treatment of cancer by the intravenous administration of highly concentrated aqueous solutions of antineoplaston A10 and antineoplaston A82-1 with high flow rates and high daily doses of the present invention leads to a partial or complete response in almost 50% of the evaluated patients with minimal adverse reactions.

Example 2. Phase II of clinical trials of antineoplaston A10 and A82-1 was performed in twelve patients with advanced stage glioma. Seven patients were diagnosed with polymorphic glioblastoma, four patients were diagnosed with anaplastic astrocytoma, and one patient was diagnosed with glioma of the brain stem with multiple metastases.

Patients received continuous infusions of antineoplaston A10 and A 82-1 for 41 days to 713 days. Doses of antineoplaston A10 ranged from 0.9 g / kg / day to 1.7 g / kg / day, and doses of A82-1 ranged from 0.2 g / kg / day to 0.8 g / kg / day.

Cases of adverse reactions to drugs of a weak nature and a single manifestation were noted in five patients in the study. Two patients showed a weak, temporary decrease in the number of white blood cells, and one patient showed a temporary decrease in the number of red blood cells and hemoglobin. Two patients had hypokalemia and hypoglycemia, one patient had increased fluid retention, and one patient had stomach cramps and nausea once during treatment.

A complete response was observed in two patients, and a partial response was observed in two patients. Four patients had stabilization, and four patients had a progressive disease.

Example 3. Phase II trials of antineoplaston A10 and A82-1 were performed on 11 patients with brain tumors. Doses of antineoplaston A10 ranged from 3.9 to 12.9 g / kg / day and doses of A82-1 ranged from 0.20 to 0.40 g / kg / day. Eight patients were evaluated. At the end of treatment, a partial response was observed in five patients.

Patients suffered from brain tumors. The injections of antineoplaston A10 and A82-1 were performed 6 times x day at a speed of 250 ml / h using a subclavian catheter and a two-channel infusion pump, as described in example 1. The duration of treatment ranged from 44 days to 480 days with an average treatment duration of 195 days . Doses of antineoplaston A10 ranged from 3.9 to 12.9 g / kg / day with an average dose of 7.2 g / kg / day. Doses of A82-1 were equal from 0.20 to 0.40 g / kg / day with an average dose of 0.29 g / kg / day. The maximum total dose of antineoplaston A10 was 381.738 kg and the maximum total dose of A82-1 was 9.702 kg.

Of the eight patients evaluated in the study, a partial response was observed in five patients, a stable disease was observed in two patients, and one patient developed a progressive disease.

Several cases of possible adverse reactions to drugs consisting of hypernatremia, hypochloremia, increased creatinine, allergies, drowsiness, weakness, fever and arthralgia have been identified. The manifestation of adverse reactions to drugs was weak and did not have a significant effect on the continuation of treatment; in particular, there were two cases of hypernatremia with rates no higher than 150 meq / l and four cases no higher than 160 meq / l. One case of hypochloremia with 82 meq / l was established, as were three cases of hypokalemia with indicators no lower than 2.5 meq / l.

Therefore, the treatment of cancer by the intravenous administration of highly concentrated aqueous solutions of antineoplaston A10 and antineoplaston A82-1 with high flow rates and high daily doses of the present invention led to a partial or complete response in 62.5% of the evaluated patients with minimal adverse reactions to the drugs.

Example 4. Phase II trials of antineoplaston A10 and A82-1 were performed in 15 patients with glioma of the brain stem. Doses of antineoplaston A10 ranged from 5.27 to 16.06 g / kg / day, and doses of A82-1 ranged from 0.20 to 0.57 g / kg / day. A complete response was observed in two patients and two patients received a partial response.

Fifteen patients with gliomas of the brain stem were admitted to the study, of which 14 were evaluated. Patients received injections of antineoplaston A10 and A82-1 6 times a day, as described in example 1. Doses of antineoplaston A10 ranged from 5.27 to 16.06 g / kg / day with an average dose of 9.47 g / kg / day . Doses of A82-1 ranged from 0.20 to 0.57 g / kg / day with an average dose of 0.37 g / kg / day. The maximum total dose of antineoplaston A10 was 311.985 kg and A82-1 - 9.912 kg.

Of the 14 patients evaluated, a complete response was observed in two patients and in two patients received a partial response according to the definitions presented in Example 1. A stable disease was observed in five patients, and five patients developed a progressive disease.

Several cases of adverse reactions to drugs have been identified, possibly related to treatment with antineoplaston A10 and A82-1. They consisted of hypernatremia, hypokalemia, allergic skin rashes, increased transaminase activity, drowsiness, weakness, shortness of breath, nausea and vomiting, diarrhea, fever and arthralgia. There were eight cases of hypernatremia with rates no higher than 150 meq / l, three cases no higher than 165 meq / l and one case 189 meq / l. In two cases, hypokalemia was established no lower than 2.5 meq / l. Cases of adverse reactions to drugs were weak and did not significantly affect the continuation of treatment.

Consequently, the treatment of cancer by intravenous administration of highly concentrated aqueous solutions of antineoplaston A10 and antineoplaston A82-1 with high flow rates and high daily doses of the present invention led to a partial or complete response in almost 30% of the evaluated patients with minimal adverse reactions to the drugs.

Example 5. Phase II trials of antineoplaston A10 and A82-1 were performed in 12 adult patients with mixed glioma. Nine patients were evaluated. Doses of antineoplaston A10 ranged from 3.5 to 12.1 g / kg / day, and doses of A82-1 ranged from 0.24 to 0.40 g / kg / day. Of the nine patients evaluated, a full response was found in three patients, and one patient received a partial response.

Patients received injections of antineoplaston A10 and A82-1, as described in example 1. The duration of treatment ranged from 32 days to 615 days with an average duration of treatment of 191 days. Doses of antineoplaston A10 ranged from 3.5 to 12.1 g / kg / day with an average dose of 7.6 g / kg / day. Doses of A82-1 ranged from 0.24 to 0.40 g / kg / day with an average dose of 0.33 g / kg / day. The maximum total dose of antineoplaston A10 was 192.907 kg, and for A82-1 it was 11.189 kg.

Of the 12 patients, nine were evaluated. Of the nine, a complete response was established in three patients, and one patient received a partial response according to the definitions given in Example 1. A stable disease was observed in two patients, and three patients developed a progressive disease.

Faced with several cases of adverse reactions to drugs, which may be associated with treatment with antineoplaston A10 and A82-1. They consisted of hypernatremia, hyperchloremia, hypokalemia, diarrhea and nausea. There were eight cases of hypernatremia with rates no higher than 150 meq / l and two cases no higher than 160 meq / l. One case of hyperchloremia with 111 meq / l and hypokalemia with 3.1 meq / l were observed. Cases of adverse reactions to drugs were weak and did not have a significant effect on the continued administration of antineoplastons.

Summary of clinical trial toxicity observations

The incidence of adverse reactions to drugs was analyzed according to data collected from 1003 patients with various types of malignant diseases registered in 67 protocols of phase II trials approved by the RIA. Some, but not all, phase II protocols are described in detail in the examples above. Due to the fact that in many cases, patients who participated in clinical trials suffered from cancer in the later stages with the likelihood of a short life expectancy, it was often difficult to establish such effects due to the late stages of the disease or the course of treatment with antineoplastons. In any case, only 1.7% of patients experienced severe toxicity (stages 3 or 4).

In phase II clinical trials of antineoplastone A10 and A82-1, and also with special exceptions, 0.3% of patients experienced stage 4 toxicity, in particular there were isolated cases of hypernatremia, thrombocytopenia and hyperbilirubinemia. 1.4% of patients had stage 3 toxicity, in particular hypernatremia, hypocalcemia, hypokalemia, hypomagnesemia, increased activity of serum glutamatoxaloacetate transaminase, or increased serum glutamate pyruvate transaminase activity.

Stage 2 toxicity was observed in 18.6% of patients, and it included fever in the absence of infection (3.3%), hypokalemia (3.0%), hypernatremia (2.0%), hypochloremia (1.9%) and neurocortical symptoms such as confusion, drowsiness (1.5%). 0.50.9% of patients experienced allergies, hypomagnesemia, neural hearing symptoms, vomiting, neurocerebral symptoms such as dizziness and slurred speech, nausea, or hyperchloremia. Less than 0.5% of patients had reduced hemoglobin, hypocalcemia, increased serum glutamate pyruvate transaminase activity, fluid retention, neuromotor weakness, or neurosighted symptoms; isolated cases of chills, diarrhea, granulocytopenia, leukopenia, lymphocytopenia, headache, polynephropathy, and increased serum glutamate-oxaloacetate-transaminase activity were also observed.

The majority of patients experienced stage I toxicity in the form of laboratory abnormalities and minor symptoms, including hypernatremia (54.3%), hypokalemia (18.0%), allergies (14.2%), neurocortical symptoms (9.1%), neuromotor weakness (7.8%), vomiting (7.6%), hypochloremia (7.1%), nausea without vomiting (6.8%) and fever in the absence of infection (6.0%). Local toxicity was observed in 7.5% of patients, most often in the form of arthralgia with myalgia, arthritis, erythema nodosum was also observed.

Additional toxicity of stage I was observed in 1.0-5.0% of patients with hyperchloremia, headache, neurocerebral symptoms, diarrhea, fluid retention, hypomagnesemia, neural hearing symptoms,

Claims (17)

Formula of the Invention by Hyponatremia and Dyspnea. Rare (less than 1.0%) cases of adverse reactions to drugs included hypocalcemia, chills, constipation, neurotensive symptoms, increased activity of serum glutamate-oxaloacetate transaminase and serum glutamate-pyruvate transaminase, hypertension, increased epidermization, thrombocytopenia and single cases of increased activity of alkaline phosphatase, bilirubin, creatinine or granulocytopenia, increased hemoglobin and hypercalcemia. Almost all patients experienced increased diuresis (98.3%) and a slight thirst, most likely due to the introduction of large volumes of fluids intravenously. The high incidence of hypernatremia is most likely due to the intake of antineoplastons in the form of sodium salts, dehydration and malignant tumors, especially the brain and liver. The maximum doses administered were 25 g / kg / day of antineoplaston A10 and 2.59 g / kg / day of A82-1. All compositions and methods disclosed and claimed in the claims, can be obtained and performed without undue experimentation in the light of the present disclosure. Although the compositions and methods of this invention have been disclosed in terms of preferred embodiments, it will be apparent to those skilled in the art that changes to the compositions and methods can be used in the steps or in the steps of the process described herein without departing from the concept of the invention . More specifically, it will be apparent that some drugs that are chemically and physiologically similar can replace the drugs described herein while the same or similar results are achieved. It is believed that all such similar substituents and modifications obvious to specialists in this field are within the nature, scope and concept of the invention defined by the attached claims. Literature The following literature sources, to the extent that they provide exemplary methodological or other details additional to those defined hereinafter, are incorporated by reference. Vsh ^ pzkts. 8. Ra1ei1 4470970. ΒιπζνηδΚί e1 a1., Aegidh Exp. 11.S1sh.Kem, 12 8irr1. 1, 25-35 (1986). Вш ^ п5к1 е1 а1., (Aegidkh Exp1kC1t.Kem, 12 8irr1. 1, 11-16 (1986)). 8ash16, i. 8. Ra1ep1 5605930. 1. Pharmaceutical composition comprising in aqueous solution a) a compound of formula I where η is 0-5; M is hydrogen, forming a salt with a cation, (C1-6) alkyl, cycloalkyl, or ( _{C6-1 2} ) aryl; K and Κι are independently selected from the group consisting of H, lower (C1 _-6 ) alkoxy and lower (C1 _-6 ) alkyl; K ₂ is selected from Formula II wherein X is halogen, lower (C1 _-6) alkyl, lower (C1-6) alkoxy, cycloalkyl, cycloalkoxy, (C 1 _{6 2)} aryl or hydroxy and η is 0, 1, 2 3 or 4; and B) a compound of formula III where η is 0-5; M is hydrogen, salt forming cation, (C _1-6) alkyl, cycloalkyl, or (C _6- 1 of ₂₎ aryl; K and K! independently selected from the group consisting of H, lower (C1 _-6 ) alkoxy and lower (C1 _-6 ) alkyl; K _{2 is} selected from formula II; in which the compound of formula I is in a 4: 1 ratio by weight to the compound of formula III and the combined concentration of the compound of formula I and the compound of formula III is from 200 to 350 mg / ml. 2. The pharmaceutical composition according to claim 1, in which in the compound of formula I M is hydrogen or sodium; η is 0; K is H or C ₃ H ₇ ; K _{1 is} selected from the group consisting of H, CH ₃ , CH ₃ —O—, C ₂ H ₅ and C ₃ H ₇ ; K _{2 is} selected from formula II, where X is C1, B or OH and where in the compound of formula III, M is hydrogen or sodium; η is 0; K is selected from the group consisting of H and C3H7; K1 is selected from the group consisting of H, CH3, CH3-O-, C2H3 and C3H7; K2 is selected from formula II, where X is C1, B or OH. 3. The pharmaceutical composition according to claim 1, in which the compound of formula I is phenylacetylglutamine or its pharmaceutically acceptable salts, and the compound of formula III is phenylacetylisoglutamine or its pharmaceutically acceptable salts. 4. The pharmaceutical composition according to claim 2 or 3, in which the combined concentration is 300 mg / ml 5. A method of treating a neoplastic disease, comprising: a) administering to the patient a pharmaceutical composition comprising: ί) the compound of formula IV 'K to ₂ - s ^ ( ^CH ^ n ohm 1, Υ where η is 0-5; M is hydrogen, forming a salt with a cation, (C1 _- b) alkyl, cycloalkyl or ( _C6-12 ) aryl; K and K _{1 are} independently selected from the group consisting of H, lower (C _1-6 ) alkoxy and lower (C _1-6 ) alkyl; K _{2 is} selected from formula II where X is halogen, lower (C _1-6 ) alkyl, lower (C1-6) alkoxy, cycloalkyl, cycloalkoxy, (C _6-12 ) aryl or hydroxy, and η is 0, 1, 2 3 or 4; and ίί) a compound of formula I wherein η is 0-5; M is hydrogen, forming a salt with a cation, (C _1-6 ) alkyl, cycloalkyl or (C _6-12 ) aryl; K and K _{1 are} independently selected from the group consisting of H, lower (C _1-6 ) alkoxy and lower (C _1-6 ) alkyl; K _{2 is} selected from formula II, wherein the compound of formula IV and the compound of formula I are in a 4: 1 ratio by weight; and ϊϊΐ) water sufficient to form an aqueous solution of a compound of formula IV and a compound of formula I, wherein the combined concentration of a compound of formula IV and a compound of formula I is from 70 to 150 mg / ml, B) administering the composition at an infusion rate of from 100 to 400 ml / h, preferably at an infusion rate of from 250 to 300 ml / h, and administering the composition at a rate sufficient to achieve a dosage level of from 0.1 to 2.6 g / kg / day, preferably the dosage level is from 0.2 to 0.9 g / kg / day. 6. The method according to claim 5, where in the compound of formula IV, M is hydrogen or sodium; η is 0; K is H or C ₃ H ₇ ; K _{1 is} selected from the group consisting of H, CH ₃ , CH ₃ —O—, C ₂ H ₅ and C ₃ H ₇ ; K _{2 is} selected from formula II, where X is C1, P or OH; and in which, in the compound of formula I, M is hydrogen or sodium; η is 0; K is H and C ₃ H ₇ ; K _{1 is} selected from the group consisting of H, CH3, CH3-O-, C2H5 and C ₃ H ₇ ; K _{2 is} selected from the substituents of formula II, where X is C1, P or OH. 7. The method according to claim 5, in which the compound of formula IV is phenylacetic acid or its pharmaceutically acceptable salts and the compound of formula I is phenylacetylglutamine or its pharmaceutically acceptable salts. 8. A pharmaceutical composition comprising in an aqueous solution: a) a compound of formula IV η "R— * 1 8 where η is 0-5; M is hydrogen, forming a salt with a cation, (C1-6) alkyl, cycloalkyl or ( _C6-12 ) aryl; K and K _{1 are} independently selected from the group consisting of H, lower (C ₁ 6) alkoxy and lower (C1-6) alkyl; K2 is selected from formula II where X is halogen, lower (C _1-6 ) alkyl, lower (C _1-6 ) alkoxy, cycloalkyl, cycloalkoxy, (C _6-12 ) aryl or hydroxy, and η is 0, 1, 2 3 or 4; B) a compound of formula III where η is 0-5; M is hydrogen, forming a salt with a cation, (C _1-6 ) alkyl, cycloalkyl or (C6-12) aryl; K and K1 are independently selected from the group consisting of H, lower (C ₁₆ ) alkoxy and lower (C _1-6 ) alkyl; K _{2 is} selected from formula II; and in which the compound of formula IV and the compound of formula III are in a 4: 1 ratio by weight and the combined concentration of the compound of formula IV and the compound of formula III is from 70 to 150 mg / ml. 9. The pharmaceutical composition of claim 8, wherein in the compound of formula IV, M is hydrogen or sodium; η is 0; K is H or C ₃ H ₇ ; K _{1 is} selected from the group consisting of H, CH ₃ , CH ₃ —O—, C ₂ H ₅ and C ₃ H ₇ ; K _{2 is} selected from formula II, where X is C1, P or OH; and where in the compound of formula III, M is hydrogen or sodium; η is 0; K is H or C3H7; K1 is selected from the group consisting of H, CH3, CH3-O-, C2H5 and C3H7; K2 is selected from formula II, where X is C1, P or OH. 10. The pharmaceutical composition of claim 8, in which the compound of formula IV is phenylacetic acid or its pharmaceutically acceptable salts, and the compound of formula III is phenylacetyl isoglutamine or its pharmaceutically acceptable salts. 11. The pharmaceutical composition according to any one of claims 7 or 10, in which the combined concentration is 80 mg / ml. 12. A pharmaceutical composition comprising phenylacetylglutamine or phenylacetylisoglutamine and water sufficient to form an aqueous solution with a concentration of 200 to 350 mg / ml. 13. A method of treating a neoplastic disease, comprising: a) administering a pharmaceutical composition according to any one of claims 1 to 4 or 12 to a patient with an infusion rate of from 100 to 400 ml / h, preferably with an infusion rate of from 250 to 300 ml / h; moreover, the composition is administered at a speed sufficient to achieve a dosage level of from 0.6 to 25 g / kg / day, preferably from 5.0 to 12.0 g / kg / day. 14. A method of treating a neoplastic disease, comprising: a) administering a pharmaceutical composition according to any one of claims 8-12 to a patient with an infusion rate of from 100 to 400 ml / h, preferably with an infusion rate of from 250 to 300 ml / h; moreover, the composition is administered at a speed sufficient to achieve a dosage level of from 0.1 to 2.6 g / kg / day, preferably from 0.2 to 0.9 g / kg / day. 15. A pharmaceutical composition comprising an aqueous solution of a compound of formula IV wherein η is 0-5; M is hydrogen, forming a salt with a cation, ( _C1-6 ) alkyl, cycloalkyl or ( _{C6-1 2} ) aryl; K and Κι are independently selected from the group consisting of H, lower (C1 _-6 ) alkoxy and lower (C1 _-6 ) alkyl; K _{2 is} selected from substituents of formula II wherein X is halogen, lower (C1 _-6 ) alkyl, lower (C1 _-6 ) alkoxy, cycloalkyl, cycloalkoxy, aryl or hydroxy, and η is 0, 1, 2, 3, or 4; and in which the concentration of the compounds of formula IV is from 70 to 150 mg / ml 16. The composition of claim 15, wherein the compound of formula IV is phenylacetic acid or pharmaceutically acceptable salts thereof. 17. The composition according to clause 15, in which the compound of formula IV is a precursor of phenylacetic acid, preferably phenylbutyric acid or its pharmaceutically acceptable salts.